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1. Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Author

Zheng, Sean L., Henry, Albert, Cannie, Douglas, Lee, Michael, Miller, David, McGurk, Kathryn A., Bond, Isabelle, Xu, Xiao, Issa, Hanane, Francis, Catherine, De Marvao, Antonio, Theotokis, Pantazis I., Buchan, Rachel J., Speed, Doug, Abner, Erik, Adams, Lance, Aragam, Krishna G., Ärnlöv, Johan, Raja, Anna Axelsson, Backman, Joshua D., Baksi, John, Barton, Paul J. R., Biddinger, Kiran J., Boersma, Eric, Brandimarto, Jeffrey, Brunak, Søren, Bundgaard, Henning, Carey, David J., Charron, Philippe, Cook, James P., Cook, Stuart A., Denaxas, Spiros, Deleuze, Jean-François, Doney, Alexander S., Elliott, Perry, Erikstrup, Christian, Esko, Tõnu, Farber-Eger, Eric H., Finan, Chris, Garnier, Sophie, Ghouse, Jonas, Giedraitis, Vilmantas, Guðbjartsson, Daniel F., Haggerty, Christopher M., Halliday, Brian P., Helgadottir, Anna, Hemingway, Harry, Hillege, Hans L., Kardys, Isabella, Lind, Lars, Lindgren, Cecilia M., Lowery, Brandon D., Manisty, Charlotte, Margulies, Kenneth B., Moon, James C., Mordi, Ify R., Morley, Michael P., Morris, Andrew D., Morris, Andrew P., Morton, Lori, Noursadeghi, Mahdad, Ostrowski, Sisse R., Owens, Anjali T., Palmer, Colin N. A., Pantazis, Antonis, Pedersen, Ole B. V., Prasad, Sanjay K., Shekhar, Akshay, Smelser, Diane T., Srinivasan, Sundararajan, Stefansson, Kari, Sveinbjörnsson, Garðar, Syrris, Petros, Tammesoo, Mari-Liis, Tayal, Upasana, Teder-Laving, Maris, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Tragante, Vinicius, Trégouët, David-Alexandre, Treibel, Thomas A., Ullum, Henrik, Valdes, Ana M., van Setten, Jessica, van Vugt, Marion, Veluchamy, Abirami, Verschuren, W. M. Monique, Villard, Eric, Yang, Yifan, Asselbergs, Folkert W., Cappola, Thomas P., Dube, Marie-Pierre, Dunn, Michael E., Ellinor, Patrick T., Hingorani, Aroon D., Lang, Chim C., Samani, Nilesh J., Shah, Svati H., Smith, J. Gustav, Vasan, Ramachandran S., O’Regan, Declan P., Holm, Hilma, Noseda, Michela, Wells, Quinn, Ware, James S., and Lumbers, R. Thomas

Published
2024
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2. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, and Stott, David J

Subjects
Regeneron Genetics Center, Humans, Atrial Fibrillation, Cardiomyopathies, Microfilament Proteins, Adaptor Proteins, Signal Transducing, Carrier Proteins, Muscle Proteins, Risk Factors, Case-Control Studies, Ventricular Function, Left, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Coronary Artery Disease, Heart Failure, Genome-Wide Association Study, Mendelian Randomization Analysis, Adaptor Proteins, Signal Transducing, Ventricular Function, Left
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Published
2020

3. Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease

Author

Horowitz, Julie E., Kosmicki, Jack A., Damask, Amy, Sharma, Deepika, Roberts, Genevieve H. L., Justice, Anne E., Banerjee, Nilanjana, Coignet, Marie V., Yadav, Ashish, Leader, Joseph B., Marcketta, Anthony, Park, Danny S., Lanche, Rouel, Maxwell, Evan, Knight, Spencer C., Bai, Xiaodong, Guturu, Harendra, Sun, Dylan, Baltzell, Asher, Kury, Fabricio S. P., Backman, Joshua D., Girshick, Ahna R., O’Dushlaine, Colm, McCurdy, Shannon R., Partha, Raghavendran, Mansfield, Adam J., Turissini, David A., Li, Alexander H., Zhang, Miao, Mbatchou, Joelle, Watanabe, Kyoko, Gurski, Lauren, McCarthy, Shane E., Kang, Hyun M., Dobbyn, Lee, Stahl, Eli, Verma, Anurag, Sirugo, Giorgio, Ritchie, Marylyn D., Jones, Marcus, Balasubramanian, Suganthi, Siminovitch, Katherine, Salerno, William J., Shuldiner, Alan R., Rader, Daniel J., Mirshahi, Tooraj, Locke, Adam E., Marchini, Jonathan, Overton, John D., Carey, David J., Habegger, Lukas, Cantor, Michael N., Rand, Kristin A., Hong, Eurie L., Reid, Jeffrey G., Ball, Catherine A., Baras, Aris, Abecasis, Gonçalo R., and Ferreira, Manuel A. R.

Published
2022
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4. Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure

Author

Levin, Michael G., Tsao, Noah L., Singhal, Pankhuri, Liu, Chang, Vy, Ha My T., Paranjpe, Ishan, Backman, Joshua D., Bellomo, Tiffany R., Bone, William P., Biddinger, Kiran J., Hui, Qin, Dikilitas, Ozan, Satterfield, Benjamin A., Yang, Yifan, Morley, Michael P., Bradford, Yuki, Burke, Megan, Reza, Nosheen, Charest, Brian, Judy, Renae L., Puckelwartz, Megan J., Hakonarson, Hakon, Khan, Atlas, Kottyan, Leah C., Kullo, Iftikhar, Luo, Yuan, McNally, Elizabeth M., Rasmussen-Torvik, Laura J., Day, Sharlene M., Do, Ron, Phillips, Lawrence S., Ellinor, Patrick T., Nadkarni, Girish N., Ritchie, Marylyn D., Arany, Zoltan, Cappola, Thomas P., Margulies, Kenneth B., Aragam, Krishna G., Haggerty, Christopher M., Joseph, Jacob, Sun, Yan V., Voight, Benjamin F., and Damrauer, Scott M.

Published
2022
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5. Exome sequencing and analysis of 454,787 UK Biobank participants

Author

Backman, Joshua D., Li, Alexander H., Marcketta, Anthony, Sun, Dylan, Mbatchou, Joelle, Kessler, Michael D., Benner, Christian, Liu, Daren, Locke, Adam E., Balasubramanian, Suganthi, Yadav, Ashish, Banerjee, Nilanjana, Gillies, Christopher E., Damask, Amy, Liu, Simon, Bai, Xiaodong, and Hawes, Alicia

Subjects
Exome sequencing -- Methods, Genetic variation -- Identification and classification, Gene banks -- Usage, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A major goal in human genetics is to use natural variation to understand the phenotypic consequences of altering each protein-coding gene in the genome. Here we used exome sequencing.sup.1 to explore protein-altering variants and their consequences in 454,787 participants in the UK Biobank study.sup.2. We identified 12 million coding variants, including around 1 million loss-of-function and around 1.8 million deleterious missense variants. When these were tested for association with 3,994 health-related traits, we found 564 genes with trait associations at P [less than or equal to] 2.18 × 10.sup.-11. Rare variant associations were enriched in loci from genome-wide association studies (GWAS), but most (91%) were independent of common variant signals. We discovered several risk-increasing associations with traits related to liver disease, eye disease and cancer, among others, as well as risk-lowering associations for hypertension (SLC9A3R2), diabetes (MAP3K15, FAM234A) and asthma (SLC27A3). Six genes were associated with brain imaging phenotypes, including two involved in neural development (GBE1, PLD1). Of the signals available and powered for replication in an independent cohort, 81% were confirmed; furthermore, association signals were generally consistent across individuals of European, Asian and African ancestry. We illustrate the ability of exome sequencing to identify gene-trait associations, elucidate gene function and pinpoint effector genes that underlie GWAS signals at scale. Whole-exome sequencing analysis of 454,787 individuals in the UK Biobank is used to examine the association of protein-coding variants with nearly 4,000 health-related traits, identifying 564 distinct genes with significant trait associations., Author(s): Joshua D. Backman [sup.1] , Alexander H. Li [sup.1] , Anthony Marcketta [sup.1] , Dylan Sun [sup.1] , Joelle Mbatchou [sup.1] , Michael D. Kessler [sup.1] , Christian Benner [...]

Published
2021
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6. Exome sequencing and characterization of 49,960 individuals in the UK Biobank

Author

Van Hout, Cristopher V., Tachmazidou, Ioanna, Backman, Joshua D., Hoffman, Joshua D., Liu, Daren, Pandey, Ashutosh K., and Gonzaga-Jauregui, Claudia

Subjects
Exome sequencing -- Analysis, Human genome -- Collections and collecting, Gene banks -- Collections and collecting, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world.sup.1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community. Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community., Author(s): Cristopher V. Van Hout [sup.1] , Ioanna Tachmazidou [sup.2] [sup.10] , Joshua D. Backman [sup.1] , Joshua D. Hoffman [sup.3] [sup.11] , Daren Liu [sup.1] , Ashutosh K. Pandey [...]

Published
2020
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7. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology

Author

Nielsen, Jonas B., Thorolfsdottir, Rosa B., Fritsche, Lars G., Zhou, Wei, Skov, Morten W., Graham, Sarah E., Herron, Todd J., McCarthy, Shane, Schmidt, Ellen M., Sveinbjornsson, Gardar, Surakka, Ida, Mathis, Michael R., Yamazaki, Masatoshi, Crawford, Ryan D., Gabrielsen, Maiken E., Skogholt, Anne Heidi, Holmen, Oddgeir L., Lin, Maoxuan, Wolford, Brooke N., Dey, Rounak, Dalen, Håvard, Sulem, Patrick, Chung, Jonathan H., Backman, Joshua D., Arnar, David O., Thorsteinsdottir, Unnur, Baras, Aris, O’Dushlaine, Colm, Holst, Anders G., Wen, Xiaoquan, Hornsby, Whitney, Dewey, Frederick E., Boehnke, Michael, Kheterpal, Sachin, Mukherjee, Bhramar, Lee, Seunggeun, Kang, Hyun M., Holm, Hilma, Kitzman, Jacob, Shavit, Jordan A., Jalife, José, Brummett, Chad M., Teslovich, Tanya M., Carey, David J., Gudbjartsson, Daniel F., Stefansson, Kari, Abecasis, Gonçalo R., Hveem, Kristian, and Willer, Cristen J.

Published
2018
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8. Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Author

Kosmicki, Jack A., Horowitz, Julie E., Banerjee, Nilanjana, Lanche, Rouel, Marcketta, Anthony, Maxwell, Evan, Bai, Xiaodong, Sun, Dylan, Backman, Joshua D., Sharma, Deepika, Kury, Fabricio S.P., Kang, Hyun M., O’Dushlaine, Colm, Yadav, Ashish, Mansfield, Adam J., Li, Alexander H., Watanabe, Kyoko, Gurski, Lauren, McCarthy, Shane E., Locke, Adam E., Khalid, Shareef, O’Keeffe, Sean, Mbatchou, Joelle, Chazara, Olympe, Huang, Yunfeng, Kvikstad, Erika, O’Neill, Amanda, Nioi, Paul, Parker, Meg M., Petrovski, Slavé, Runz, Heiko, Szustakowski, Joseph D., Wang, Quanli, Wong, Emily, Cordova-Palomera, Aldo, Smith, Erin N., Szalma, Sandor, Zheng, Xiuwen, Esmaeeli, Sahar, Davis, Justin W., Lai, Yi-Pin, Chen, Xing, Justice, Anne E., Leader, Joseph B., Mirshahi, Tooraj, Carey, David J., Verma, Anurag, Sirugo, Giorgio, Ritchie, Marylyn D., Rader, Daniel J., Povysil, Gundula, Goldstein, David B., Kiryluk, Krzysztof, Pairo-Castineira, Erola, Rawlik, Konrad, Pasko, Dorota, Walker, Susan, Meynert, Alison, Kousathanas, Athanasios, Moutsianas, Loukas, Tenesa, Albert, Caulfield, Mark, Scott, Richard, Wilson, James F., Baillie, J. Kenneth, Butler-Laporte, Guillaume, Nakanishi, Tomoko, Lathrop, Mark, Richards, J. Brent, Jones, Marcus, Balasubramanian, Suganthi, Salerno, William, Shuldiner, Alan R., Marchini, Jonathan, Overton, John D., Habegger, Lukas, Cantor, Michael N., Reid, Jeffrey G., Baras, Aris, Abecasis, Goncalo R., and Ferreira, Manuel A.R.

Published
2021
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9. Genome-wide association study of liver fat, iron, and extracellular fluid fraction in the UK Biobank

Author

O’Dushlaine, Colm, primary, Germino, Mary, additional, Verweij, Niek, additional, Nielsen, Jonas B., additional, Yadav, Ashish, additional, Benner, Christian, additional, Backman, Joshua D., additional, Lin, Nan, additional, R. Abecasis, Gonçalo, additional, Baras, Aris, additional, Ferreira, Manuel A., additional, Lotta, Luca A., additional, Walls, Johnathon R., additional, Parasoglou, Prodromos, additional, and Marchini, Jonathan L., additional

Published
2021
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10. Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients

Author

Lewis, Joshua P, Backman, Joshua D, Reny, Jean-Luc, Bergmeijer, Thomas O, Mitchell, Braxton D, Ritchie, Marylyn D, Déry, Jean-Pierre, Pakyz, Ruth E, Gong, Li, Ryan, Kathleen, Kim, Eun-Young, Aradi, Daniel, Fernandez-Cadenas, Israel, Lee, Ming Ta Michael, Whaley, Ryan M, Montaner, Joan, Gensini, Gian Franco, Cleator, John H, Chang, Kiyuk, Holmvang, Lene, Hochholzer, Willibald, Roden, Dan M, Winter, Stefan, Altman, Russ B, Alexopoulos, Dimitrios, Kim, Ho-Sook, Gawaz, Meinrad, Bliden, Kevin P, Valgimigli, Marco, Marcucci, Rossella, et al, University of Zurich, and Lewis, Joshua P

Subjects
2736 Pharmacology (medical), 610 Medicine & health, 11171 Cardiocentro Ticino, 2705 Cardiology and Cardiovascular Medicine
Published
2020
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11. The genomics of heart failure : design and rationale of the HERMES consortium

Author

Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner‐La Rocca, Hans‐Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B., Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Giedraitis, Vilmantas, Lind, Lars, Smith, J. Gustav, Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner‐La Rocca, Hans‐Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B., Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Giedraitis, Vilmantas, Lind, Lars, and Smith, J. Gustav

Abstract

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Published
2021
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12. The genomics of heart failure:design and rationale of the HERMES consortium

Author

Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner-La Rocca, Hans Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., de Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Ghanbari, Mohsen, Kardys, Isabella, Kavousi, Maryam, Portilla-Fernandez, Eliana, Teumer, Alexander, Uitterlinden, Andre G., Yang, Jian, Vasan, RS, Smith, JG, Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner-La Rocca, Hans Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., de Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Ghanbari, Mohsen, Kardys, Isabella, Kavousi, Maryam, Portilla-Fernandez, Eliana, Teumer, Alexander, Uitterlinden, Andre G., Yang, Jian, Vasan, RS, and Smith, JG

Abstract

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Published
2021

13. Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel:A Study by the International Clopidogrel Pharmacogenomics Consortium

Author

Verma, Shefali Setia, Bergmeijer, Thomas O., Gong, Li, Reny, Jean Luc, Lewis, Joshua P., Mitchell, Braxton D., Alexopoulos, Dimitrios, Aradi, Daniel, Altman, Russ B., Bliden, Kevin, Bradford, Yuki, Campo, Gianluca, Chang, Kiyuk, Cleator, John H., Déry, Jean Pierre, Dridi, Nadia P., Fernandez-Cadenas, Israel, Fontana, Pierre, Gawaz, Meinrad, Geisler, Tobias, Gensini, Gian Franco, Giusti, Betti, Gurbel, Paul A., Hochholzer, Willibald, Holmvang, Lene, Kim, Eun Young, Kim, Ho Sook, Marcucci, Rossella, Montaner, Joan, Backman, Joshua D., Pakyz, Ruth E., Roden, Dan M., Schaeffeler, Elke, Schwab, Matthias, Shin, Jae Gook, Siller-Matula, Jolanta M., ten Berg, Jurriën M., Trenk, Dietmar, Valgimigli, Marco, Wallace, John, Wen, Ming Shien, Kubo, Michiaki, Lee, Ming Ta Michael, Whaley, Ryan, Winter, Stefan, Klein, Teri E., Shuldiner, Alan R., Ritchie, Marylyn D., Verma, Shefali Setia, Bergmeijer, Thomas O., Gong, Li, Reny, Jean Luc, Lewis, Joshua P., Mitchell, Braxton D., Alexopoulos, Dimitrios, Aradi, Daniel, Altman, Russ B., Bliden, Kevin, Bradford, Yuki, Campo, Gianluca, Chang, Kiyuk, Cleator, John H., Déry, Jean Pierre, Dridi, Nadia P., Fernandez-Cadenas, Israel, Fontana, Pierre, Gawaz, Meinrad, Geisler, Tobias, Gensini, Gian Franco, Giusti, Betti, Gurbel, Paul A., Hochholzer, Willibald, Holmvang, Lene, Kim, Eun Young, Kim, Ho Sook, Marcucci, Rossella, Montaner, Joan, Backman, Joshua D., Pakyz, Ruth E., Roden, Dan M., Schaeffeler, Elke, Schwab, Matthias, Shin, Jae Gook, Siller-Matula, Jolanta M., ten Berg, Jurriën M., Trenk, Dietmar, Valgimigli, Marco, Wallace, John, Wen, Ming Shien, Kubo, Michiaki, Lee, Ming Ta Michael, Whaley, Ryan, Winter, Stefan, Klein, Teri E., Shuldiner, Alan R., and Ritchie, Marylyn D.

Abstract

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e−33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e−09, 4.53e−08, and 2.60e−10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.

Published
2020

14. Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients

Author

Lewis, Joshua P., Backman, Joshua D., Reny, Jean Luc, Bergmeijer, Thomas O., Mitchell, Braxton D., Ritchie, Marylyn D., Déry, Jean Pierre, Pakyz, Ruth E., Gong, Li, Ryan, Kathleen, Kim, Eun Young, Aradi, Daniel, Fernandez-Cadenas, Israel, Lee, Ming Ta Michael, Whaley, Ryan M., Montaner, Joan, Franco Gensini, Gian, Cleator, John H., Chang, Kiyuk, Holmvang, Lene, Hochholzer, Willibald, Roden, Dan M., Winter, Stefan, Altman, Russ B., Alexopoulos, Dimitrios, Kim, Ho Sook, Gawaz, Meinrad, Bliden, Kevin P., Valgimigli, Marco, Marcucci, Rossella, Campo, Gianluca, Schaeffeler, Elke, Dridi, Nadia P., Wen, Ming Shien, Shin, Jae Gook, Fontana, Pierre, Giusti, Betti, Geisler, Tobias, Kubo, Michiaki, Trenk, Dietmar, Siller-Matula, Jolanta M., Ten Berg, Jurriën M., Gurbel, Paul A., Schwab, Matthias, Klein, Teri E., Shuldiner, Alan R., Lewis, Joshua P., Backman, Joshua D., Reny, Jean Luc, Bergmeijer, Thomas O., Mitchell, Braxton D., Ritchie, Marylyn D., Déry, Jean Pierre, Pakyz, Ruth E., Gong, Li, Ryan, Kathleen, Kim, Eun Young, Aradi, Daniel, Fernandez-Cadenas, Israel, Lee, Ming Ta Michael, Whaley, Ryan M., Montaner, Joan, Franco Gensini, Gian, Cleator, John H., Chang, Kiyuk, Holmvang, Lene, Hochholzer, Willibald, Roden, Dan M., Winter, Stefan, Altman, Russ B., Alexopoulos, Dimitrios, Kim, Ho Sook, Gawaz, Meinrad, Bliden, Kevin P., Valgimigli, Marco, Marcucci, Rossella, Campo, Gianluca, Schaeffeler, Elke, Dridi, Nadia P., Wen, Ming Shien, Shin, Jae Gook, Fontana, Pierre, Giusti, Betti, Geisler, Tobias, Kubo, Michiaki, Trenk, Dietmar, Siller-Matula, Jolanta M., Ten Berg, Jurriën M., Gurbel, Paul A., Schwab, Matthias, Klein, Teri E., and Shuldiner, Alan R.

Abstract

Aims Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19∗2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. Methods and results We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N= 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19∗2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19∗17, P = 9.5 × 10-10; CYP2B6 1294 53C> T, P = 3.0 × 10-4; CYP2B6 516G> T, P = 1.0 × 10-3; CYP2C9∗2, P = 1.2 × 10-3; and CYP2C9∗3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (b = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (b = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. Conclusion Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future prec

Published
2020

15. Genome‐wide association analysis of serum alanine and aspartate aminotransferase, and the modifying effects of BMI in 388k European individuals.

Author

Gao, Chuan, Marcketta, Anthony, Backman, Joshua D., O'Dushlaine, Colm, Staples, Jeffrey, Ferreira, Manuel Allen Revez, Lotta, Luca A., Overton, John D., Reid, Jeffrey G., Mirshahi, Tooraj, Regeneron Genetics Center, Geisinger Regeneron Discovehr Collaboration, Baras, Aris, Abecasis, Gonçalo, Shuldiner, Alan R., Van Hout, Cristopher V., and McCarthy, Shane

Published
2021
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16. Genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation

Author

Nielsen, Jonas B., primary, Thorolfsdottir, Rosa B., additional, Fritsche, Lars G., additional, Zhou, Wei, additional, Skov, Morten W., additional, Graham, Sarah E., additional, Herron, Todd J., additional, McCarthy, Shane, additional, Schmidt, Ellen M., additional, Sveinbjornsson, Gardar, additional, Surakka, Ida, additional, Mathis, Michael R., additional, Yamazaki, Masatoshi, additional, Crawford, Ryan D., additional, Gabrielsen, Maiken E., additional, Skogholt, Anne Heidi, additional, Holmen, Oddgeir L., additional, Lin, Maoxuan, additional, Wolford, Brooke N., additional, Dey, Rounak, additional, Dalen, Håvard, additional, Sulem, Patrick, additional, Chung, Jonathan H., additional, Backman, Joshua D., additional, Arnar, David O., additional, Thorsteinsdottir, Unnur, additional, Baras, Aris, additional, O’Dushlaine, Colm, additional, Holst, Anders G., additional, Wen, Xiaoquan, additional, Hornsby, Whitney, additional, Dewey, Frederick E., additional, Boehnke, Michael, additional, Kheterpal, Sachin, additional, Lee, Seunggeun, additional, Kang, Hyun M., additional, Holm, Hilma, additional, Kitzman, Jacob, additional, Shavit, Jordan A., additional, Jalife, José, additional, Brummett, Chad M., additional, Teslovich, Tanya M., additional, Carey, David J., additional, Gudbjartsson, Daniel F., additional, Stefansson, Kari, additional, Abecasis, Goncalo R., additional, Hveem, Kristian, additional, and Willer, Cristen J., additional

Published
2018
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17. Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation

Author

Chen, Ming-Huei, primary, Yanek, Lisa R., additional, Backman, Joshua D., additional, Eicher, John D., additional, Huffman, Jennifer E., additional, Ben-Shlomo, Yoav, additional, Beswick, Andrew D., additional, Yerges-Armstrong, Laura M., additional, Shuldiner, Alan R., additional, O’Connell, Jeffrey R., additional, Mathias, Rasika A., additional, Becker, Diane M., additional, Becker, Lewis C., additional, Lewis, Joshua P., additional, Johnson, Andrew D., additional, and Faraday, Nauder, additional

Published
2017
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18. Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response

Author

Backman, Joshua D., primary, O’Connell, Jeffrey R., additional, Tanner, Keith, additional, Peer, Cody J., additional, Figg, William D., additional, Spencer, Shawn D., additional, Mitchell, Braxton D., additional, Shuldiner, Alan R., additional, Yerges-Armstrong, Laura M., additional, Horenstein, Richard B., additional, and Lewis, Joshua P., additional

Published
2017
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19. Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation.

Author

Chen, Ming-Huei, Eicher, John D., Huffman, Jennifer E., Johnson, Andrew D., Yanek, Lisa R., Becker, Diane M., Backman, Joshua D., Yerges-Armstrong, Laura M., Shuldiner, Alan R., O'Connell, Jeffrey R., Lewis, Joshua P., Ben-Shlomo, Yoav, Beswick, Andrew D., Mathias, Rasika A., Becker, Lewis C., and Faraday, Nauder

Subjects
BLOOD platelet aggregation, META-analysis
Abstract

Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10-7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20-50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study. [ABSTRACT FROM AUTHOR]

Published
2019
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20. From Genotype to Phenotype: Nonsense Variants in SLC13A1 Are Associated with Decreased Serum Sulfate and Increased Serum Aminotransferases

Author

Tise, Christina G, primary, Perry, James A, additional, Anforth, Leslie E, additional, Pavlovich, Mary A, additional, Backman, Joshua D, additional, Ryan, Kathleen A, additional, Lewis, Joshua P, additional, O’Connell, Jeffrey R, additional, Yerges-Armstrong, Laura M, additional, and Shuldiner, Alan R, additional

Published
2016
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22. Genetic Variation in the Platelet Endothelial Aggregation Receptor 1 Gene Results in Endothelial Dysfunction

Author

Fisch, Adam S., primary, Yerges-Armstrong, Laura M., additional, Backman, Joshua D., additional, Wang, Hong, additional, Donnelly, Patrick, additional, Ryan, Kathleen A., additional, Parihar, Ankita, additional, Pavlovich, Mary A., additional, Mitchell, Braxton D., additional, O’Connell, Jeffrey R., additional, Herzog, William, additional, Harman, Christopher R., additional, Wren, Jonathan D., additional, and Lewis, Joshua P., additional

Published
2015
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23. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, and Lumbers, R Thomas

Subjects
2. Zero hunger, Cyclin-Dependent Kinase Inhibitor p21, Heart Failure, Microfilament Proteins, Muscle Proteins, Coronary Artery Disease, Mendelian Randomization Analysis, Ventricular Function, Left, 3. Good health, Risk Factors, Case-Control Studies, Atrial Fibrillation, Humans, Apoptosis Regulatory Proteins, Cardiomyopathies, Carrier Proteins, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

24. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K., Wilk, Jemma B., Morley, Michael P., Chaffin, Mark D., Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G., Ärnlöv, Johan, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Brandimarto, Jeffrey, Brown, Michael R., Buckbinder, Leonard, Carey, David J., Chasman, Daniel I., Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P., Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Dunn, Michael E., Engström, Gunnar, Esko, Tõnu, Felix, Stephan B., Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S., Gross, Stefan, Guðbjartsson, Daníel F., Gutmann, Rebecca, Haggerty, Christopher M., Van Der Harst, Pim, Hyde, Craig L., Ingelsson, Erik, Jukema, J. Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E., Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M., London, Barry, Lotta, Luca A., Lovering, Ruth C., Luan, Jian’an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B., März, Winfried, Melander, Olle, Mordi, Ify R., Morgan, Thomas, Morris, Andrew D., Morris, Andrew P., Morrison, Alanna C., Nagle, Michael W., Nelson, Christopher P., Niessner, Alexander, Niiranen, Teemu, O’Donoghue, Michelle L., Owens, Anjali T., Palmer, Colin N. A., Parry, Helen M., Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M., Rice, Kenneth M., Ridker, Paul M., Romaine, Simon P. R., Rotter, Jerome I., Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A., Smelser, Diane T., Smith, Nicholas L., Stender, Steen, Stott, David J., Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D., Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G., Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A., Wang, Xiaosong, Wareham, Nicholas J., Waterworth, Dawn, Weeke, Peter E., Weiss, Raul, Wiggins, Kerri L., Xing, Heming, Yerges-Armstrong, Laura M., Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J., McMurray, John J. V., Yang, Jian, Visscher, Peter M., Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A., Sattar, Naveed, Holmes, Michael V., Cappola, Thomas P., Asselbergs, Folkert W., Hingorani, Aroon D., Kuchenbaecker, Karoline, Ellinor, Patrick T., Lang, Chim C., Stefansson, Kari, Smith, J. Gustav, Vasan, Ramachandran S., Swerdlow, Daniel I., Lumbers, R. Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M., Habegger, Lukas, Hahn, Young, Hawes, Alicia, Van Hout, Cristopher, Jones, Marcus B., Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K., McCarthy, Shane, Mitnaul, Lyndon J., O’Dushlaine, Colm, Overton, John D., Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G., Schleicher, Thomas D., Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C., Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H., Widom, Louis, Wolf, Sarah E., Yadav, Ashish, and Ye, Bin

Subjects
2. Zero hunger, 631/443/592/2727, 631/208/205/2138, 692/699/75/230, 45/43, article, 692/308/174, 3. Good health
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

25. The genomics of heart failure: design and rationale of the HERMES consortium

Author

Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner‐La Rocca, Hans‐Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., De Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B., Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S., Gross, Stefan, Guðbjartsson, Daníel F., Gui, Hongsheng, Gutmann, Rebecca, Haggerty, Christopher M., Van Der Harst, Pim, Hedman, Åsa K., Helgadottir, Anna, Hillege, Hans, Hyde, Craig L., Jacob, Jaison, Jukema, J. Wouter, Kamanu, Frederick, Kardys, Isabella, Kavousi, Maryam, Khaw, Kay‐Tee, Kleber, Marcus E., Køber, Lars, Koekemoer, Andrea, Kraus, Bill, Kuchenbaecker, Karoline, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M., London, Barry, Lotta, Luca A., Lovering, Ruth C., Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Mann, Douglas, Margulies, Kenneth B., Marston, Nicholas A., März, Winfried, McMurray, John J.V., Melander, Olle, Melloni, Giorgio, Mordi, Ify R., Morley, Michael P., Morris, Andrew D., Morris, Andrew P., Morrison, Alanna C., Nagle, Michael W., Nelson, Christopher P., Newton‐Cheh, Christopher, Niessner, Alexander, Niiranen, Teemu, Nowak, Christoph, O'Donoghue, Michelle L., Owens, Anjali T., Palmer, Colin N.A., Paré, Guillaume, Perola, Markus, Perreault, Louis‐Philippe Lemieux, Portilla‐Fernandez, Eliana, Psaty, Bruce M., Rice, Kenneth M., Ridker, Paul M., Romaine, Simon P.R., Roselli, Carolina, Rotter, Jerome I., Ruff, Christian T., Sabatine, Marc S., Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A., Smelser, Diane T., Smith, Nicholas L., Stefansson, Kari, Stender, Steen, Stott, David J., Sveinbjörnsson, Garðar, Tammesoo, Mari‐Liis, Tardif, Jean‐Claude, Taylor, Kent D., Teder‐Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp‐Pedersen, Christian, Trompet, Stella, Tuckwell, Danny, Tyl, Benoit, Uitterlinden, Andre G., Vaura, Felix, Veluchamy, Abirami, Visscher, Peter M., Völker, Uwe, Voors, Adriaan A., Wang, Xiaosong, Wareham, Nicholas J., Weeke, Peter E., Weiss, Raul, White, Harvey D., Wiggins, Kerri L., Xing, Heming, Yang, Jian, Yang, Yifan, Yerges‐Armstrong, Laura M., Yu, Bing, Zannad, Faiez, Zhao, Faye, Regeneron Genetics Center, Wilk, Jemma B., Holm, Hilma, Sattar, Naveed, Lubitz, Steven A., Lanfear, David E., Shah, Svati, Dunn, Michael E., Wells, Quinn S., Asselbergs, Folkert W., Hingorani, Aroon D., Dubé, Marie‐Pierre, Samani, Nilesh J., Lang, Chim C., Cappola, Thomas P., Ellinor, Patrick T., Vasan, Ramachandran S., and Smith, J. Gustav

Subjects
Study Design, Cardiomyopathy, FOS: Biological sciences, Study Designs, Genetics, Heart failure, Biomarkers, 3. Good health, Association studies
Abstract

Funder: Knut and Alice Wallenberg Foundation; Id: http://dx.doi.org/10.13039/501100004063, Funder: Swedish National Health Service, Funder: Skåne University Hospital; Id: http://dx.doi.org/10.13039/501100011077, Funder: Crafoord Foundation; Id: http://dx.doi.org/10.13039/501100003173, Funder: Department of Medicine, Boston University School of Medicine; Id: http://dx.doi.org/10.13039/100008748, Funder: Evans Medical Foundation; Id: http://dx.doi.org/10.13039/100015927, Funder: National Heart, Lung, and Blood Institute; Id: http://dx.doi.org/10.13039/100000050, Funder: British Heart Foundation Cardiovascular Biomedicine, Funder: NIHR UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012317, Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

26. The genomics of heart failure: design and rationale of the HERMES consortium

Author

Lumbers, R Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I, Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V, Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G, Asselin, Geraldine, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R, Brunner-La Rocca, Hans-Peter, Carey, David J, Chaffin, Mark D, Chasman, Daniel I, Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H, Chutkow, William, Cleland, John GF, Cook, James P, De Denus, Simon, Dehghan, Abbas, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B, Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gui, Hongsheng, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hedman, Åsa K, Helgadottir, Anna, Hillege, Hans, Hyde, Craig L, Jacob, Jaison, Jukema, J Wouter, Kamanu, Frederick, Kardys, Isabella, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Kraus, Bill, Kuchenbaecker, Karoline, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Mann, Douglas, Margulies, Kenneth B, Marston, Nicholas A, März, Winfried, McMurray, John JV, Melander, Olle, Melloni, Giorgio, Mordi, Ify R, Morley, Michael P, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Newton-Cheh, Christopher, Niessner, Alexander, Niiranen, Teemu, Nowak, Christoph, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Paré, Guillaume, Perola, Markus, Perreault, Louis-Philippe Lemieux, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Roselli, Carolina, Rotter, Jerome I, Ruff, Christian T, Sabatine, Marc S, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stefansson, Kari, Stender, Steen, Stott, David J, Sveinbjörnsson, Garðar, Tammesoo, Mari-Liis, Tardif, Jean-Claude, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tuckwell, Danny, Tyl, Benoit, Uitterlinden, Andre G, Vaura, Felix, Veluchamy, Abirami, Visscher, Peter M, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Weeke, Peter E, Weiss, Raul, White, Harvey D, Wiggins, Kerri L, Xing, Heming, Yang, Jian, Yang, Yifan, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Faye, Regeneron Genetics Center, Wilk, Jemma B, Holm, Hilma, Sattar, Naveed, Lubitz, Steven A, Lanfear, David E, Shah, Svati, Dunn, Michael E, Wells, Quinn S, Asselbergs, Folkert W, Hingorani, Aroon D, Dubé, Marie-Pierre, Samani, Nilesh J, Lang, Chim C, Cappola, Thomas P, Ellinor, Patrick T, Vasan, Ramachandran S, and Smith, J Gustav

Subjects
Aged, 80 and over, Heart Failure, Male, Cardiomyopathy, Genomics, Middle Aged, 16. Peace & justice, Prognosis, 3. Good health, FOS: Biological sciences, Genetics, Humans, Female, Biomarkers, Association studies, Aged, Genome-Wide Association Study
Abstract

AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10-8 under an additive genetic model. CONCLUSIONS: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

27. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin N A, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon P R, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John J V, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, and Lumbers, R Thomas

Subjects
2. Zero hunger, 3. Good health
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

28. The genomics of heart failure: design and rationale of the HERMES consortium.

Author

Lumbers RT, Shah S, Lin H, Czuba T, Henry A, Swerdlow DI, Mälarstig A, Andersson C, Verweij N, Holmes MV, Ärnlöv J, Svensson P, Hemingway H, Sallah N, Almgren P, Aragam KG, Asselin G, Backman JD, Biggs ML, Bloom HL, Boersma E, Brandimarto J, Brown MR, Brunner-La Rocca HP, Carey DJ, Chaffin MD, Chasman DI, Chazara O, Chen X, Chen X, Chung JH, Chutkow W, Cleland JGF, Cook JP, de Denus S, Dehghan A, Delgado GE, Denaxas S, Doney AS, Dörr M, Dudley SC, Engström G, Esko T, Fatemifar G, Felix SB, Finan C, Ford I, Fougerousse F, Fouodjio R, Ghanbari M, Ghasemi S, Giedraitis V, Giulianini F, Gottdiener JS, Gross S, Guðbjartsson DF, Gui H, Gutmann R, Haggerty CM, van der Harst P, Hedman ÅK, Helgadottir A, Hillege H, Hyde CL, Jacob J, Jukema JW, Kamanu F, Kardys I, Kavousi M, Khaw KT, Kleber ME, Køber L, Koekemoer A, Kraus B, Kuchenbaecker K, Langenberg C, Lind L, Lindgren CM, London B, Lotta LA, Lovering RC, Luan J, Magnusson P, Mahajan A, Mann D, Margulies KB, Marston NA, März W, McMurray JJV, Melander O, Melloni G, Mordi IR, Morley MP, Morris AD, Morris AP, Morrison AC, Nagle MW, Nelson CP, Newton-Cheh C, Niessner A, Niiranen T, Nowak C, O'Donoghue ML, Owens AT, Palmer CNA, Paré G, Perola M, Perreault LL, Portilla-Fernandez E, Psaty BM, Rice KM, Ridker PM, Romaine SPR, Roselli C, Rotter JI, Ruff CT, Sabatine MS, Salo P, Salomaa V, van Setten J, Shalaby AA, Smelser DT, Smith NL, Stefansson K, Stender S, Stott DJ, Sveinbjörnsson G, Tammesoo ML, Tardif JC, Taylor KD, Teder-Laving M, Teumer A, Thorgeirsson G, Thorsteinsdottir U, Torp-Pedersen C, Trompet S, Tuckwell D, Tyl B, Uitterlinden AG, Vaura F, Veluchamy A, Visscher PM, Völker U, Voors AA, Wang X, Wareham NJ, Weeke PE, Weiss R, White HD, Wiggins KL, Xing H, Yang J, Yang Y, Yerges-Armstrong LM, Yu B, Zannad F, Zhao F, Wilk JB, Holm H, Sattar N, Lubitz SA, Lanfear DE, Shah S, Dunn ME, Wells QS, Asselbergs FW, Hingorani AD, Dubé MP, Samani NJ, Lang CC, Cappola TP, Ellinor PT, Vasan RS, and Smith JG

Subjects
Aged, Aged, 80 and over, Female, Genomics, Humans, Male, Middle Aged, Prognosis, Genome-Wide Association Study, Heart Failure genetics
Abstract

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure., Methods and Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 -8 under an additive genetic model., Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Published
2021
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29. Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.

Author

Verma SS, Bergmeijer TO, Gong L, Reny JL, Lewis JP, Mitchell BD, Alexopoulos D, Aradi D, Altman RB, Bliden K, Bradford Y, Campo G, Chang K, Cleator JH, Déry JP, Dridi NP, Fernandez-Cadenas I, Fontana P, Gawaz M, Geisler T, Gensini GF, Giusti B, Gurbel PA, Hochholzer W, Holmvang L, Kim EY, Kim HS, Marcucci R, Montaner J, Backman JD, Pakyz RE, Roden DM, Schaeffeler E, Schwab M, Shin JG, Siller-Matula JM, Ten Berg JM, Trenk D, Valgimigli M, Wallace J, Wen MS, Kubo M, Lee MTM, Whaley R, Winter S, Klein TE, Shuldiner AR, and Ritchie MD

Subjects
Aged, Blood Platelets metabolism, Cardiovascular Diseases blood, Cardiovascular Diseases genetics, Cardiovascular Diseases mortality, Clopidogrel adverse effects, Coronary Artery Disease mortality, Cytochrome P-450 CYP2C19 metabolism, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Pharmacogenetics, Platelet Aggregation Inhibitors adverse effects, Risk Assessment, Risk Factors, Treatment Outcome, Blood Platelets drug effects, Cardiovascular Diseases prevention & control, Clopidogrel therapeutic use, Coronary Artery Disease therapy, Cytochrome P-450 CYP2C19 genetics, Percutaneous Coronary Intervention adverse effects, Percutaneous Coronary Intervention mortality, Pharmacogenomic Variants, Platelet Aggregation Inhibitors therapeutic use, Polymorphism, Single Nucleotide
Abstract

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Published
2020
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30. Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients.

Author

Lewis JP, Backman JD, Reny JL, Bergmeijer TO, Mitchell BD, Ritchie MD, Déry JP, Pakyz RE, Gong L, Ryan K, Kim EY, Aradi D, Fernandez-Cadenas I, Lee MTM, Whaley RM, Montaner J, Gensini GF, Cleator JH, Chang K, Holmvang L, Hochholzer W, Roden DM, Winter S, Altman RB, Alexopoulos D, Kim HS, Gawaz M, Bliden KP, Valgimigli M, Marcucci R, Campo G, Schaeffeler E, Dridi NP, Wen MS, Shin JG, Fontana P, Giusti B, Geisler T, Kubo M, Trenk D, Siller-Matula JM, Ten Berg JM, Gurbel PA, Schwab M, Klein TE, and Shuldiner AR

Subjects
Aged, Brain Ischemia mortality, Brain Ischemia prevention & control, Clopidogrel adverse effects, Coronary Artery Disease blood, Coronary Artery Disease diagnosis, Coronary Artery Disease mortality, Coronary Thrombosis mortality, Coronary Thrombosis prevention & control, Europe, Female, Humans, Male, Middle Aged, Myocardial Infarction mortality, Myocardial Infarction prevention & control, Platelet Aggregation genetics, Platelet Aggregation Inhibitors adverse effects, Predictive Value of Tests, Risk Assessment, Risk Factors, Stents, Stroke mortality, Stroke prevention & control, Treatment Outcome, Clopidogrel therapeutic use, Coronary Artery Disease therapy, Decision Support Techniques, Percutaneous Coronary Intervention adverse effects, Percutaneous Coronary Intervention instrumentation, Percutaneous Coronary Intervention mortality, Pharmacogenomic Variants, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors therapeutic use, Polymorphism, Single Nucleotide
Abstract

Aims: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial., Methods and Results: We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles., Conclusion: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Published
2020
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31. From Genotype to Phenotype: Nonsense Variants in SLC13A1 Are Associated with Decreased Serum Sulfate and Increased Serum Aminotransferases.

Author

Tise CG, Perry JA, Anforth LE, Pavlovich MA, Backman JD, Ryan KA, Lewis JP, O'Connell JR, Yerges-Armstrong LM, and Shuldiner AR

Subjects
Acetaminophen adverse effects, Adult, Aged, Amish genetics, Animals, Bone Density genetics, Calcium blood, Cation Transport Proteins blood, Chemical and Drug Induced Liver Injury genetics, Chemical and Drug Induced Liver Injury pathology, Dogs, Female, Heterozygote, Humans, Intestinal Mucosa metabolism, Kidney metabolism, Liver drug effects, Liver pathology, Male, Membrane Transport Proteins blood, Middle Aged, Sheep, Sodium Sulfate Cotransporter, Sulfate Transporters, Sulfates blood, Symporters blood, Transaminases blood, Cation Transport Proteins genetics, Codon, Nonsense genetics, Membrane Transport Proteins genetics, Polymorphism, Single Nucleotide genetics, Symporters genetics
Abstract

Using genomic applications to glean insights into human biology, we systematically searched for nonsense single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two nonlinked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. SLC13A1 R12X and W48X were independently associated with a 27.6% (P = 2.7 × 10(-8)) and 27.3% (P = 6.9 × 10(-14)) decrease in serum sulfate, respectively (P = 8.8 × 10(-20) for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P = 4.4 × 10(-12)). Consistent with sulfate's role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to noncarriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally occurring, homozygous, loss-of-function mutations in Slc13a1 This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity., (Copyright © 2016 Tise et al.)

Published
2016
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